Methods of sedation during critical care treatment

ABSTRACT

Methods of sedating a patient undergoing critical care treatment using intravenous gaboxadol are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/834,027, filed Aug. 24, 2015, which claims benefit of and priority toU.S. Provisional Application No. 62/203,748, filed Aug. 11, 2015, theentire contents of which are incorporated herein by reference.

TECHNICAL FIELD

Methods of sedating a patient undergoing critical care treatment usinggaboxadol or a pharmaceutically acceptable salt thereof are provided.

BACKGROUND

Critically ill patients are routinely provided analgesia and sedation toprevent pain and anxiety during invasive procedures. There is currentlyno universally accepted sedative regimen for critically ill patients.Thus, patients often receive a variety of drugs during their stay in anintensive care unit, often receiving a variety of drugs concurrently.Moreover, over sedation may occur leading to longer time on mechanicalventilation, prolonged stay in the intensive care unit, and increasedbrain dysfunction (e.g., delirium and coma). For many years, sedationguidelines have supported the use of gamma-aminobutyric-acid(GABA)-receptor agonists, including propofol and benzodiazepines (e.g.,midazolam) for targeted sedation of ICU patients. However, these agentsare associated with adverse effects such as respiratory depression,hypotension, bradycardia, hyperlipidemia, lack of orientation, andpotential abuse. Accordingly, there remains a need in the art for safeand effective methods of sedating a patient undergoing critical caretreatment.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol) (THIP)),described in U.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO2005/094820, is a selective GABA_(A) receptor agonist with a preferencefor δ-subunit containing GABA_(A) receptors. In the early 1980sgaboxadol was the subject of a series of pilot studies that tested itsefficacy as an analgesic and anxiolytic, as well as a treatment fortardive dyskinesia, Huntington's disease, Alzheimer's disease, andspasticity. In the 1990s gaboxadol moved into late stage development forthe treatment of insomnia but failed to show significant effects insleep onset and sleep maintenance in a three-month efficacy study.Additionally, patients with a history of drug abuse who receivedgaboxadol experienced a steep increase in psychiatric adverse events. Asa result of these negative results the development of gaboxadol wasterminated. It has now been found that gaboxadol may provide a safe andeffective alternative for the sedation of patients undergoing criticalcare treatment.

SUMMARY

Provided herein are methods of critical care sedation of a patient byadministering to the patient a pharmaceutical composition of gaboxadolor a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Provided herein are methods of critical care sedation of a patient byadministering to the patient a pharmaceutical composition of gaboxadolor a pharmaceutically acceptable salt thereof. Critical care sedationherein includes, but is not limited to, intensive care sedation;sedation of the patient prior to or during surgery; procedural sedation;monitored anesthesia care; combined sedation and regional anesthesia;induction of general anesthesia; maintenance of general anesthesia;initiation of monitored anesthesia care; maintenance of monitoredanesthesia care; general anesthesia; moderate sedation; and conscioussedation. Thus, embodiments include methods of critical care sedation byadministering to the patient a pharmaceutical composition of gaboxadolor a pharmaceutically acceptable salt thereof wherein the critical caresedation is selected from the group selected from intensive caresedation, sedation of the patient prior to or during surgery, proceduralsedation, monitored anesthesia care, general anesthesia, moderatesedation, and conscious sedation.

In embodiments, critical care sedation herein includes Intensive CareUnit (ICU) sedation. ICU sedation is typically administered to patientsto help the patient sleep but still be able to respond to nursing staff(e.g., light sedation). In embodiments, critical care sedation hereininvolves procedural sedation. In embodiments, the methods involvesedation of initially intubated and mechanically ventilated patientsduring treatment in an intensive care setting. In embodiments, themethods include sedation of non-intubated patients prior to and/orduring surgical and other procedures.

In embodiments, critical care sedation herein involves Moderate Sedationor Conscious Sedation. During Moderate Sedation or Conscious Sedation aphysician supervises or personally administers sedative and/or analgesicmedications that can allay patient anxiety and control pain during adiagnostic or therapeutic procedure. Such drug-induced depression of apatient's level of consciousness to a “moderate” level of sedation, asdefined in the Joint Commission standards, is intended to facilitate thesuccessful performance of the diagnostic or therapeutic procedure whileproviding patient comfort and cooperation.

In embodiments, critical care sedation involves Monitored AnesthesiaCare. Monitored Anesthesia Care (MAC) is a specific anesthesia servicethat involves an anesthesiologist administering sedatives and analgesicsto a patient while monitoring his/her vital signs. Monitored AnesthesiaCare is often used to supplement local and regional anesthesia fornon-intubated patients undergoing non-invasive procedures and minorsurgery. The goal of Monitored Anesthesia Care is to relieve anxiety byinducing a minimally depressed level of consciousness while the patientis able to continuously and independently maintain an open airway and torespond appropriately to verbal commands.

An important component of MAC is the anesthesia assessment andmanagement of a patient's actual or anticipated medical problems thatmay occur during a diagnostic or therapeutic procedure. While MonitoredAnesthesia Care may include the administration of sedatives and/oranalgesics often used for Moderate Sedation, the provider of MAC must beprepared and qualified to convert to general anesthesia when necessary.By contrast, Moderate Sedation is not expected to induce depths ofsedation that could impair the patient's ability to maintain theintegrity of his or her airway.

The administration of sedatives, hypnotics, analgesics, as well asanesthetic drugs commonly used for the induction and maintenance ofgeneral anesthesia is often, but not always, a part of MonitoredAnesthesia Care. In some patients who may require only minimal sedation,MAC is often indicated because even small doses of these medicationscould precipitate adverse physiologic responses that would necessitateacute clinical interventions and resuscitation.

The precise amount of gaboxadol administered herein is dependent onnumerous factors, such as the general condition of the patient, thecondition to be treated, the desired duration of use, the route ofadministration, etc. The amount of gaboxadol may also be dependent onwhether the sedation includes a single administration of gaboxadol toachieve sedation or a combination of an initiation dosage to achievesedation and a maintenance dosage to continue sedation in the patient.Thus, the amount of gaboxadol used may be dependent on whether theadministration is during an initiation dosage or a maintenance dosage.In embodiments, the methods involve administration of a singleinitiation dosage to provide critical care sedation. In embodiments, themethods involve administration of an initiation dosage followed byadministration of a maintenance dosage to continue critical caresedation. As used herein an initiation dosage may also be referred to asa loading dosage that is administered as an initial higher dose ofgaboxadol and may be given at the beginning of treatment before droppingdown to a lower maintenance dose. The maintenance dosage may beadministered immediately following the initiation dosage or may beseparated by a period of time, e.g., 1 minute, 5 minutes, 10 minutes, 15minutes etc.

The initiation and/or the maintenance dosage of gaboxadol may beprovided in one or more administrations to provide the desired amount ofsedation. In embodiments, a bolus dose may be used to administer aninitiation dosage. In embodiments, one or more intermittent bolus dosesmay be used to administer a maintenance dose. In embodiments, a bolusdose may be used to administer an initiation dosage and treatmentcontinued by a steady maintenance infusion. In embodiments, amaintenance dosage may be administered by adjusting the rate ofintravenous administrations to one or more administration ratesdescribed below.

In embodiments, deuterated gaboxadol may be used. Deuteration ofpharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD),and toxicity profiles, has been demonstrated previously with someclasses of drugs. Accordingly the use of deuterium enriched gaboxadol iscontemplated and within the scope of the methods and compositionsdescribed herein. Deuterium can be incorporated in any position inreplace of hydrogen synthetically, according to the synthetic proceduresknown in the art. For example, deuterium may be incorporated to variouspositions having an exchangeable proton, such as the amine N—H, viaproton-deuterium equilibrium exchange. Thus, deuterium may beincorporated selectively or non-selectively through methods known in theart to provide deuterium enriched gaboxadol. See Journal of LabeledCompounds and Radiopharmaceuticals 19(5) 689-702 (1982).

Deuterium enriched gaboxadol may be described by the percentage ofincorporation of deuterium at a given position in the molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat that specified position. The deuterium enrichment can be determinedusing conventional analytical methods, such as mass spectrometry andnuclear magnetic resonance spectroscopy. In embodiments deuteriumenriched gaboxadol means that the specified position is enriched withdeuterium above the naturally occurring distribution (i.e., above about0.0156%). In embodiments deuterium enrichment is no less than about 1%,no less than about 5%, no less than about 10%, no less than about 20%,no less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, or no less than about 98% of deuterium at aspecified position.

In embodiments, the total amount of gaboxadol administered during thecritical care sedation is between about 0.1 mg to about 500 mggaboxadol. For example, the patient may be administered an initiationdose of gaboxadol of between about 1 mg to about 100 mg and then amaintenance dose of between about 1 mg to about 400 mg over a specificperiod of time, e.g., 20 minutes, 30 minutes, 45 minutes, 1 hour, 6hours, 12 hours, 24 hours, such that the patient receives a total amountof gaboxadol of between about 1 mg to about 500 mg gaboxadol.

In embodiments, the initiation dose of gaboxadol during critical caresedation may be administered intravenously by infusion or by slowinjection. In embodiments, the initiation dose may be administered as abolus dose. The initiation dosage may involve administering betweenabout 1 mg to about 100 mg gaboxadol. In embodiments, the initiationdosage includes administering an amount of gaboxadol or pharmaceuticallyacceptable salt thereof between about, e.g., 0.1 mg to 50 mg, 0.1 mg to25 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, or 0.1 mg to 5 mg. Inembodiments, the initiation dosage includes administering between about,e.g., 1 mg to 25 mg, 1 mg to 15 mg, 1 mg to 10 mg, or 1 mg to 5 mg.

In examples, the initiation dosage involves about 1 mg, about 2 mg,about 5 mg, about 10 mg, about 25 mg, about 50 mg or increments thereofof gaboxadol. In examples, the initiation dosage involves about 3 mg,about 4 mg, about 7.5 mg, about 12 mg, about 15 mg, about 20 mg, about30 mg, about 40 mg, or increments thereof of gaboxadol. In examples, theinitiation dosage may involve about 60 mg, about 65 mg, about 75 mg,about 80 mg, about 90 mg, or about 100 mg of gaboxadol. In embodiments,the initiation dosage may involve administering gaboxadol to the patientin increments of about 0.5, about 1 mg, about 2 mg, about 2.5 mg, about5 mg, about 10 mg, or about 20 mg until the desired level of sedation isachieved.

The dose range of gaboxadol administered according to the disclosureherein may also be defined according to one or more pharmacokineticparameters. In embodiments, the initiation dosage administered duringcritical care sedation may provide an in vivo plasma profile in thepatient of a C_(max) less than, e.g., about 3500 ng/ml, about 3000ng/ml, about 2500 ng/ml, about 2000 ng/ml, about 1500 ng/ml, or about1000 ng/ml. In embodiments, the initiation dosage administered duringcritical care sedation may provide an in vivo plasma profile in thepatient of a C_(max) less than, e.g., about 3250 ng/ml, about 2750ng/ml, about 2250 ng/ml, about 1750 ng/ml, about 1250 ng/ml, or about750 ng/ml. In embodiments, the initiation dosage may provide an in vivoplasma profile in the patient of a C_(max) less than, e.g., about 1000ng/ml, about 750 ng/ml, about 250 ng/ml, about 150 ng/ml, about 100ng/ml, or about 75 ng/ml. In embodiments, the initiation dosage mayprovide an in vivo plasma profile in the patient of a C_(max) less thanabout 500 ng/ml. In embodiments, the initiation dosage may provide an invivo plasma profile in the patient of a C_(max) less than about 350ng/ml.

In embodiments, the initiation dosage administered during critical caresedation may provide an in vivo plasma profile in the patient of aAUC_(0-∞) less than, e.g., about 4000 ng·hr/ml, about 3000 ng·hr/ml,about 2500 ng·hr/ml, about 2000 ng·hr/ml, about 1500 ng·hr/ml, about1000 ng·hr/ml, or about 500 ng·hr/ml. In embodiments, the initiationdosage may provide an in vivo plasma profile of a AUC_(0-∞) less thanabout 2250 ng·hr/ml. In embodiments, the initiation dosage may providean in vivo plasma profile of a AUC_(0-∞) less than about 1750 ng·hr/ml.

In embodiments, the initiation dose of gaboxadol may be administered atan infusion rate of between about 0.1 to about 1000 μg/kg/hour. Inembodiments, the initiation dose may be administered at an infusion rateof between, e.g., about 1 to about 750 μg/kg/min, about 1 to about 500μg/kg/min, about 1 to about 250 μg/kg/min, about 1 to about 100μg/kg/min, or about 1 to about 50 μg/kg/min. In other embodiments, theinitiation dose may be administered at an infusion rate of between,e.g., about 0.5 to about 250 μg/kg/min, about 0.5 to about 100μg/kg/min, about 0.5 to about 50 μg/kg/min, or about 0.5 to about 25μg/kg/min. In embodiments, the initiation dose may be administered at aninfusion rate of between, e.g., about 0.25 to about 100 μg/kg/min, about0.25 to about 75 μg/kg/min, about 0.25 to about 50 μg/kg/min, or about0.25 to about 25 μg/kg/min.

In embodiments, the initiation dose may be administered at an infusionrate of between about 25 to about 75 μg/kg/min. In embodiments, theinitiation dose may be administered at an infusion rate of between about5 to about 50 μg/kg/min. In embodiments, the infusion rate may beincreased by increments of about 5 to 10 μg/kg/min until a desired levelof sedation is achieved.

One skilled in the art will appreciate that the infusion rates may alsobe expressed as mg/kg/h. For example, in embodiments, the initiationdose may be administered at an infusion rate of between about 1 to about10 mg/kg/h, about 2 to about 10 mg/kg/h, about 5 to about 10 mg/kg/h, orabout 8 to about 10 mg/kg/h. In embodiments, the initiation dose may beadministered at an infusion rate of between about 2 to about 8 mg/kg/h,about 4 to about 8 mg/kg/h, about 5 to about 8 mg/kg/h, or about 6 toabout 10 mg/kg/h. In embodiments, the initiation dose may beadministered at an infusion rate of between about 6 to about 9 mg/kg/h(100 to 150 μg/kg/min).

In embodiments the initiation dose of gaboxadol may be administered toachieve a plasma concentration of, e.g., about 0.1 to about 25 μg/kg,about 0.1 to about 15 μg/kg, about 0.1 to about 10 μg/kg, about 0.1 toabout 5 μg/kg, about 0.2 to about 2 μg/kg, about 0.5 to about 2 μg/kg,or about 0.5 to about 1 μg/kg. In embodiments, the initiation dose maybe administered to achieve a plasma concentration of less than about 15μg/kg, less than about 10 μg/kg, less than about 5 μg/kg, less thanabout 2.5 μg/kg, or less than about 1.0 μg/kg of gaboxadol.

In embodiments, the methods provide administration of a maintenance doseof gaboxadol to provide sedation to the patient. One skilled in the artwill appreciate that the maintenance dose is dependent on numerousfactors, such as the general condition of the patient, the route ofadministration (e.g., infusion, slow injection, bolus etc.) and the typeof critical care sedation. In embodiments the initiation dosage isprovided for a period of time, e.g., over 1 minute, 2 minutes, 3minutes, 5 minutes, 10 minutes etc., followed by a maintenance dosage.The maintenance dosage may be administered immediately following theinitiation dosage or separated by a period of time, e.g., 1 minute, 2minutes, 5 minutes, 10 minutes, 15 minutes. In embodiments, themaintenance dosage may be provided for up to a specific period of time,e.g., up to 1 hour, up to 6 hours, up to 12 hours, or up to 24 hours.

In embodiments, the maintenance dose may be administered by infusion orby slow injection. In embodiments, the maintenance dose of gaboxadol maybe administered as an intermittent bolus dose. The maintenance dosagemay include administering between about 1 mg to about 100 mg gaboxadol.In embodiments, the maintenance dosage includes administering an amountof gaboxadol or pharmaceutically acceptable salt thereof between about,e.g., 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 15 mg, 0.1 mg to 10mg, or 0.1 mg to 5 mg. In embodiments, the maintenance dosage includesadministering between about, e.g., 1 mg to 25 mg, 1 mg to 15 mg, 1 mg to10 mg, or 1 mg to 5 mg.

In examples, a maintenance dosage may include administering, e.g., about1 mg, about 2 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg orincrements thereof of gaboxadol. In examples, a maintenance dosage mayinclude administering about 3 mg, about 7.5 mg, about 12 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg, or increments thereof ofgaboxadol or pharmaceutically acceptable salt thereof. In examples, amaintenance dosage may include administering about 60 mg, about 65 mg,about 75 mg, about 80 mg, about 90 mg, or about 100 mg of gaboxadol. Inembodiments, the maintenance dosage may include administering gaboxadolto the patient in increments of about 0.5 mg, 1 mg, 5 mg, about 10 mg,about 20 mg, about 25 mg, or about 50 mg.

The maintenance dosage of gaboxadol administered herein may also bedefined according to one or more pharmacokinetic parameters. Inembodiments, plasma concentrations of gaboxadol for maintenance ofsedation can be achieved by adjusting the rate of intravenousadministration or by administering intermittent bolus injections. Inembodiments, the maintenance dosage administered during critical caresedation may provide an in vivo plasma profile in the patient of aC_(max) less than, e.g., about 3500 ng/ml, about 3000 ng/ml, about 2500ng/ml, about 2000 ng/ml, about 1500 ng/ml, or about 1000 ng/ml. Inembodiments, the maintenance dosage may provide an in vivo plasmaprofile in the patient of a C_(max) less than, e.g., about 3250 ng/ml,about 2750 ng/ml, about 2250 ng/ml, about 1750 ng/ml, about 1250 ng/ml,or about 750 ng/ml. In embodiments, the maintenance dosage may providean in vivo plasma profile in the patient of a C_(max) less than, e.g.,about 1000 ng/ml, about 750 ng/ml, about 250 ng/ml, about 150 ng/ml,about 100 ng/ml, or about 75 ng/ml. In embodiments, the maintenancedosage may provide an in vivo plasma profile in the patient of a C_(max)less than about 500 ng/ml. In embodiments, the maintenance dosage mayprovide an in vivo plasma profile in the patient of a C_(max) less thanabout 250 ng/ml.

In embodiments, the maintenance dosage administered during critical caresedation may provide an in vivo plasma profile in the patient of anAUC_(0-∞) less than, e.g., about 4000 ng·hr/ml, about 3000 ng·hr/ml,about 2500 ng·hr/ml, about 2000 ng·hr/ml, about 1500 ng·hr/ml, about1000 ng·hr/ml, or about 500 ng·hr/ml. In embodiments, the maintenancedosage provides an in vivo plasma profile of a AUC_(0-∞) less than about2250 ng·hr/ml. In embodiments, the maintenance dosage may provide an invivo plasma profile in the patient of a AUC_(0-∞) less than about 1750ng·hr/ml.

In embodiments, the maintenance dose may be administered at an infusionrate of between about 0.1 to about 1000 μg/kg/hour. In embodiments, themaintenance dose may be administered at an infusion rate of between,e.g., about 1 to about 750 μg/kg/min, about 1 to about 500 μg/kg/min,about 1 to about 250 μg/kg/min, about 1 to about 100 μg/kg/min, or about1 to about 50 μg/kg/min. In embodiments, the maintenance dose may beadministered at an infusion rate of between, e.g., about 0.5 to about250 μg/kg/min, about 0.5 to about 100 μg/kg/min, about 0.5 to about 50μg/kg/min, or about 0.5 to about 25 μg/kg/min. In embodiments, themaintenance dose may be administered at an infusion rate of between,e.g., about 0.25 to about 100 μg/kg/min, about 0.25 to about 75μg/kg/min, about 0.25 to about 50 μg/kg/min, or about 0.25 to about 25μg/kg/min.

In embodiments, the maintenance dose may be administered at an infusionrate of between about 25 to about 75 μg/kg/min. In embodiments, themaintenance dose may be administered at an infusion rate of betweenabout 5 to about 50 μg/kg/min. In embodiments, the infusion rate may beincreased by increments of about 5 to 10 μg/kg/min to maintain thedesired level of sedation. One skilled in the art will appreciate thatthe infusion rates described may also be expressed as mg/kg/h. Forexample, in embodiments, the maintenance dose may be administered at aninfusion rate of between about 1 to about 10 mg/kg/h, about 2 to about10 mg/kg/h, about 5 to about 10 mg/kg/h, or about 8 to about 10 mg/kg/h.In embodiments, the maintenance dose may be administered at an infusionrate of between about 2 to about 8 mg/kg/h, about 4 to about 8 mg/kg/h,about 5 to about 8 mg/kg/h, or about 6 to about 10 mg/kg/h. Inembodiments, the maintenance dose may be administered at an infusionrate of between about 6 to about 9 mg/kg/h (100 to 150 μg/kg/min).

In embodiments the maintenance dose may be administered to maintain aplasma concentration range of the patient of, e.g., about 0.1 to about25 μg/kg, about 0.1 to about 15 μg/kg, about 0.1 to about 10 μg/kg,about 0.1 to about 5 μg/kg, about 0.2 to about 2 μg/kg, about 0.5 toabout 2 μg/kg, or about 0.5 to about 1 μg/kg of gaboxadol. In exemplaryembodiments, the maintenance dose may be less than, e.g., about 5 μg/kg,less than about 2.5 μg/kg, or less than about 1.0 μg/kg of gaboxadol.

In embodiments, gaboxadol is continuously infused in mechanicallyventilated patients prior to extubation, during extubation, andpost-extubation. In embodiments, sedation is provided wherein theinfusion does not last longer than, e.g., 6 hours, 12 hours or 24 hours.In specific examples, the methods provide infusion wherein the infusiondoes not last more than 24 hours. In embodiments, gaboxadol isadministered using a controlled infusion device. In embodiments, thegaboxadol is co-administered with an anesthetic, sedative, hypnotic, oropioid. Such co-administration may lead to an enhancement of effects orsynergistic effect resulting in increased sedative activity. Ifobserved, reduction in dosage of the amount of gaboxadol or theconcomitant anesthetic, sedative, hypnotic, or opioid may be required.

One skilled in the art will appreciate that there are numerous animalmodels that may be used to evaluate and compare the relative safety andefficacy of pharmaceutical products. Accordingly, using a relevantanimal model, one skilled in the art may be able to compare the safetyand/or effectiveness of gaboxadol relative to other sedatives. Forexample, tests of preattentive functioning have been described for micethat utilize a simple testing paradigm called prepulse inhibition (PPI).Additional paradigms include simple screens using object discriminationtests or more complex paradigms such as go/no-go testing, five-choiceserial attention tasks, or latent inhibition. In addition, tests oflearning and memory can be designed to assess more specific areas offunctioning, including associative learning, nonspatial or spatiallearning, short- and long-term memory, as well as neurologicallyspecific deficits as revealed by fear or eyelid conditioning.

One skilled in the art would expect compounds that act as GABA agoniststo provide similar efficacy and adverse event profiles. Thus, methodsherein that provide improvements in sedation and/or reduction in one ormore adverse events may be considered surprising and unexpected.Accordingly, in embodiments gaboxadol may be administered wherein themethods surprisingly and unexpectedly provide increased efficacy and/orreduced adverse events observed during critical care sedation. Forexample, the methods described herein may provide decreased incidence ofan adverse event selected from the group consisting of respiratorydepression, hypotension, bradycardia, hyperlipidemia and lack oforientation.

Moreover, it is known in the art that sedation methods may also lead toadverse events that occur after sedation or may be caused alone or inpart from sedative use. For example, patients that are administeredsedatives may experience longer time on mechanical ventilation,prolonged stay in the intensive care unit, and/or increased braindysfunction (e.g., delirium and coma). In embodiments, the methods maysurprisingly and unexpectedly provide increased efficacy and/or reducedadverse events after critical care sedation. In embodiments, criticalcare sedation is provided wherein the administration of gaboxadolprovides increased efficacy and/or reduced side effects relative to oneor more sedatives. For example, critical care sedation may be providedwherein the administration of gaboxadol provides reduced adverse eventscompared to another GABA agonist. In other examples, the administrationof gaboxadol may provide reduced adverse events compared to propofol. Instill other examples, the administration of gaboxadol may providereduced adverse events compared to midazolam. In embodiments, criticalcare sedation is provided wherein the administration of gaboxadolprovides reduced adverse events compared to dexmedetomidine. Inembodiments, the patient may be administered a pharmaceuticalcomposition including gaboxadol wherein the composition providessedation while also providing reduced adverse events compared to anotherGABA agonist.

In embodiments methods of critical care sedation are provided byadministering a pharmaceutical composition including gaboxadol whereinthere is no significant effect of at least one adverse event selectedfrom the group consisting of respiratory depression, hemodynamics,vasodilation, hypotension, bradycardia, tachycardia, atrialfibrillation, pyrexia, cognition, cognitive function, hypertension,apnea, airway obstruction, sinus arrest, oxygen desaturation, anddelirium. Cognition refers to the mental processes involved in gainingknowledge and comprehension, such as thinking, knowing, remembering,judging, and problem solving.

In embodiments, the methods include administering gaboxadol whereinthere is no substantial occurrence of at least one adverse eventselected from the group consisting of respiratory depression,hemodynamics, vasodilation, hypotension, bradycardia, tachycardia,atrial fibrillation, pyrexia, cognition, cognitive function,hypertension, apnea, airway obstruction, sinus arrest, oxygendesaturation, and delirium. In embodiments, there is no significantoccurrence of at least one adverse event selected from the groupconsisting of respiratory depression, hemodynamics, vasodilation,hypotension, bradycardia, tachycardia, atrial fibrillation, pyrexia,cognition, cognitive function, hypertension, apnea, airway obstruction,sinus arrest, oxygen desaturation, and delirium. In embodiments, themethods include administering gaboxadol wherein there is nostatistically significant occurrence of at least one adverse event. Forexample, the methods may include administering gaboxadol wherein thereis no meaningful effect on cognition. In examples, the methods mayinclude administering gaboxadol wherein the patient experiences nosignificant sinus arrest.

In embodiments, provided herein are methods of critical care sedation ofa patient by administering a pharmaceutical composition includinggaboxadol wherein respiratory depression is not substantial. Inembodiments, administration of gaboxadol to a patient results inreductions in respiratory depression relative to administration ofanother sedative, e.g., propofol, lorazepam, midazolam, and/ordexmedetomidine. In embodiments, provided herein are methods of criticalcare sedation wherein the administration results in no significantrespiratory depression. Respiratory depression is a major concern withmany sedatives (e.g., midazolam, propofol) currently used for MAC. Thereis clearly an unmet need for a sedative agent that can safely be usedduring sedation, and especially MAC, in both healthy and high-riskpopulations with limited adverse side effects. In embodiments, providedherein are methods of attenuating anxiety and/or stress associated withsurgery and/or ICU procedures wherein there is no significant occurrenceof respiratory depression.

In embodiments, provided herein are methods of critical care sedation ofa patient by administering a pharmaceutical composition includinggaboxadol wherein administration does not result in significantdelirium. Delirium acute brain dysfunction is sudden severe confusiondue to rapid changes in brain function. Delirium occurs in 60-80% ofventilated Intensive Care Unit (ICU) patients and is independentlyassociated with prolonged hospital stay, higher cost, a 3-fold increasedrisk of dying by six months and ongoing neuropsychological dysfunction.Delirium has recently been shown as a predictor of death, increasedcost, and longer length of stay in ventilated patients. Sedative andanalgesic medications relieve anxiety and pain, but may contribute topatients' transitioning into delirium. Accordingly provided herein aremethods of attenuating anxiety and/or stress associated with surgeryand/or ICU procedures without causing significant delirium.

Standard use of GABA agonist sedatives, such as lorazepam and propofol,may contribute to ICU delirium and other unwanted clinical outcomes.Provided herein are methods of sedation wherein the prevalence ofdelirium is less than with other GABA receptor agonists. In embodiments,provided herein are methods of critical care sedation wherein there is asignificant reduction of delirium compared to another GABA receptoragonist, e.g., lorazepam, propofol, midazolam. In embodiments, providedherein are methods of critical care sedation wherein the occurrence ofdelirium is significantly less than compared to another GABA receptoragonist, e.g., lorazepam, propofol, midazolam.

In embodiments, provided herein are methods of critical care sedation ofa patient wherein the patient remains arousable and oriented.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosure herein belongs.

Gaboxadol may be formulated for administration to a patient usingpharmaceutically acceptable salts including acid addition salts, azwitter ion hydrate, zwitter ion anhydrate, hydrochloride orhydrobromide salt, or in the form of the zwitter ion monohydrate. Acidaddition salts, include but are not limited to, maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acidaddition salts, as well as the 8-halotheophyllines, for example8-bromo-theophylline. In other suitable embodiments, inorganic acidaddition salts, including but not limited to, hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric or nitric acid addition salts may beused. Gaboxadol may be crystalline, such as the crystalline hydrochloricacid salt, hydrobromic acid salt, or the crystalline zwitter ionmonohydrate.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, preferably up to 10%, more preferably up to 5%,and more preferably still up to 1% of a given value. Alternatively,particularly with respect to biological systems or processes, the termcan mean within an order of magnitude, preferably within 5-fold, andmore preferably within 2-fold, of a value.

“PK” refers to the pharmacokinetic profile. C_(max) is defined as thehighest plasma drug concentration estimated during an experiment(ng/ml). T_(max) is defined as the time when C_(max) is estimated (min).AUC_(0-∞) is the total area under the plasma drug concentration-timecurve, from drug administration until the drug is eliminated (ng·hr/ml).The area under the curve is governed by clearance. Clearance is definedas the volume of blood or plasma that is totally cleared of its contentof drug per unit time (ml/min).

As used herein, the term “treating” or “treatment” refers toalleviating, attenuating or delaying the appearance of clinical symptomsof a disease or condition in a subject that may be afflicted with orpredisposed to the disease or condition, but does not yet experience ordisplay clinical or subclinical symptoms of the disease or condition. Incertain embodiments, treating” or “treatment” may refer to preventingthe appearance of clinical symptoms of a disease or condition in asubject that may be afflicted with or predisposed to the disease orcondition, but does not yet experience or display clinical orsubclinical symptoms of the disease or condition. “Treating” or“treatment” also refers to inhibiting the disease or condition, e.g.,arresting or reducing its development or at least one clinical orsubclinical symptom thereof “Treating” or “treatment” further refers torelieving the disease or condition, e.g., causing regression of thedisease or condition or at least one of its clinical or subclinicalsymptoms. The benefit to a subject to be treated may be statisticallysignificant, mathematically significant, or at least perceptible to thesubject and/or the physician. Nonetheless, prophylactic (preventive) andtherapeutic (curative) treatment are two separate embodiments of thedisclosure herein.

“Effective amount” or “therapeutically effective amount” means a dosagesufficient to alleviate one or more symptom of a disorder, disease, orcondition being treated, or to otherwise provide a desiredpharmacological and/or physiologic effect.

“Pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”—e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In another embodiment, this term refers tomolecular entities and compositions approved by a regulatory agency ofthe federal or a state government, as the GRAS list under section 204(s)and 409 of the Federal Food, Drug and Cosmetic Act, that is subject topremarket review and approval by the FDA or similar lists, the U.S.Pharmacopeia or another generally recognized pharmacopeia for use inanimals, and more particularly in humans.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the subject matter described herein. Such equivalents areintended to be encompassed by the claims.

EXAMPLES Example 1

Intravenous Tolerability of Gaboxadol

The first part of this study (Part 1) was conducted to assess theintravenous tolerability of gaboxadol. In particular, Part 1 consistedof 8 normal healthy adult subjects who received double-blindadministration of single intravenous (IV) doses of gaboxadol (5 mg and10 mg) or single IV doses of placebo (normal saline) in a fixedsequence, rising dose fashion. A second part of the study (Part 2) was a6-period crossover that consisted of 10 normal healthy adult subjectswho received double-blind administration of 5 single oral doses ofgaboxadol (2.5, 5, 10, 15, and 20 mg) randomized across Periods 1through 5, and then single-dose gaboxadol 10 mg administeredintravenously over 60 minutes in Period 6. There was a washout of 4 daysbetween each treatment period.

The study included healthy, male and female subjects between 18 and 45years of age within 30% of ideal weight. The subjects in Part 1 of thestudy could be of either gender, but within Part 2 of the study therehad to be at least 4 subjects of each gender.

In Part 1 each subject received two single IV doses of isotonicgaboxadol HCl (5 mg and 10 mg) or IV placebo (normal saline). Subjectsreceived each of the 5 oral doses (2.5, 5, 10, 15, and 20 mg) ofgaboxadol and a single IV dose of gaboxadol in Treatment Period 6 (10 mgwas selected as the IV dose based on the acceptable tolerabilitydemonstrated in Part 1 of the study). The Primary Endpoints includedgaboxadol Pharmacokinetics (dose proportionality), absolutebioavailability and tolerability, and safety following IV and oralgaboxadol.

Following single intravenous doses, gaboxadol AUC_(0-inf) and C_(max)increased with increasing dose while the other parameters (CL, t_(1/2),V_(SS), f_(e), and CL_(R)) were independent of dose. Gaboxadol exhibitedmoderate systemic clearance (CL) and moderate steady-state volume ofdistribution (V_(SS)). After oral administration, gaboxadol AUC_(0-inf)and C_(max) increased with increasing dose while the other parameters(CL/F, t_(max), t_(1/2), f_(e), and CL_(R)) were independent of dose.Oral clearance (CL/F) was of similar magnitude following oraladministration as that observed after intravenous administration,consistent with the estimated oral bioavailability of 92%. Renalclearance (CL_(R)) was greater than glomerular filtration rateindicating net secretion of gaboxadol.

These results suggest that single dose administration of intravenousgaboxadol doses of 5 and 10 mg, and single dose administration of oraldoses of gaboxadol from 2.5 to 20 mg and are generally well tolerated.There were no serious adverse experiences reported, and the most commonclinical adverse experiences reported in both parts of the study weresomnolence and dizziness.

Example 2

Assessment of Residual Effects Resulting from Gaboxadol Administration

This study was a double blind, double-dummy, randomized, active- andplacebo-controlled, single dose, 3-period crossover study, followed byan open-label, single-dose, single period study in healthy elderly maleand female subjects. Subjects were randomized to each of 3 treatments(Treatments A, B, and C) to be administered in a crossover manner overthe first 3 treatment periods. For Treatment A, subjects received asingle dose of gaboxadol 10 mg; for Treatment B, subjects received asingle dose of flurazepam 30 mg; and for Treatment C, subjects receiveda single dose of placebo. Doses were administered orally at bedtime onDay 1. Subjects were domiciled from early in the evening of dosing until˜36 hours post-dose (morning of Day 3) during each treatment period. Thesubjects who participated in treatment periods 1-3 participated in afourth treatment period. In this period, a single dose of gaboxadol 10mg (Treatment D) was administered orally in an open-label manner on themorning of Day 1 for PK of gaboxadol. There was at least a 14-daywashout between the doses of consecutive treatment periods. Studyparticipants included healthy, elderly male and female subjects between65 and 80 years of age, with a Mini Mental Status 24, weighing at least55 kg. All subjects received 10 mg gaboxadol monohydrate capsules and 30mg flurazepam (provided as 2×15 mg capsules), matching placebo wasprovided for both gaboxadol and flurazepam.

The primary endpoints evaluated included pharmacodynamics (measurementof psychomotor performance, memory, attention and daytime sleepiness thefollowing pm dosing), gaboxadol pharmacokinetics, and safety. Gaboxadol(single dose 10 mg) did not show residual effect 9 hours post-dose onthe primary endpoints Choice Reaction Time and Critical Flicker Fusion,whereas the active reference Flurazepam (30 mg single dose) showedsignificant effect on the same tests. In addition, gaboxadol did notshow any signs of residual effects on other measurements applied in thestudy (Multiple Sleep Latency Test (MSLT); Digit Symbol SubstitutionTest (DSST), Tracking, Memory tests, Body Sway, and Leeds SleepEvaluation Questionnaire).

Example 3

Study of Driving Performance after Gaboxadol Administration

This study was a double blind, randomized, placebo and active controlled5 way cross over study to investigate the effect of evening and middleof the night dosing of gaboxadol on driving performance. The studyparticipants included healthy, male and female subjects between 21 and45 years of age, with a valid drivers license for at least 3 years.

The effects of gaboxadol on driving performance were investigated usingreal driving on the road setting. Subjects received 15 mg gaboxadoleither in the evening prior to going to bed or at 4 am in the middle ofthe night following a wake-up call. Following a cognitive andpsychomotor test battery, the driving test started at 9 am and lastedfor one hour. Gaboxadol 15 mg had a clinically relevant impairing effecton driving following middle-of-the-night administration.

Following the evening dose, a statistically significant effect ofgaboxadol 15 mg was observed on driving. However, this effect was lessthan the effect observed at a 0.05% blood alcohol concentration, theconcentration limit at which driving is prohibited in most Europeancountries. There was generally a numerically greater effect followingzopiclone (7.5 mg) and zolpidem (10 mg) administered in the evening andin the middle of the night, respectively. Both the evening and themiddle-of-the-night dose of gaboxadol were well tolerated with the mostfrequent adverse events being dizziness, nausea and somnolence for themiddle-of-the-night treatment and headache and somnolence for theevening treatment.

Subjects on the active reference zopiclone had a numerically greatereffect in the same test. There was no effect on memory test, body sway,DSST or critical tracking, whereas zopiclone had effect on several ofthese tests.

Example 4

Study of Daytime Performance after Sleep Restriction

This study was a 4-night, parallel-group, randomized, double-blind (within-house blinding), placebo-controlled, fixed-dose study to assess theeffects of gaboxadol on daytime performance in healthy adults subjectedto a 5-hour sleep restriction. The study included a 2-night single-blindplacebo run-in period, a 4-night double-blind treatment period duringwhich sleep was restricted to 5 hours and a 2-night single-blind placeborun-out period. The study included healthy male and female volunteers 18to <55 years of age.

2-night run-in period: All patients received placebo

4-night double-blind treatment period: Patients were randomized togaboxadol 15 mg or matching placebo

2-night run-out period: All patients received placebo

The primary endpoints included observations based on the Multiple SleepLatency Test (MSLT) and Slow Wave Sleep (SWS) assessment. The primaryobjective was to evaluate the efficacy of gaboxadol (15 mg) compared toplacebo in reducing daytime sleep propensity as measured by MSLT. Thegaboxadol subjects had significantly less daytime sleepiness during theSleep Restriction period than did placebo subjects (p=0.047, 1 sided).The MSLT was on average 2.01 minutes longer for subjects treated withgaboxadol (15 mg) than for those with placebo on the last two SleepRestriction days.

In addition, a secondary objective was to evaluate the efficacy ofgaboxadol compared to placebo in increasing the amount of slow wavesleep (SWS) during the last 2 nights of sleep restriction. Subjectsreceiving gaboxadol experienced significantly more SWS during the SleepRestriction period than did placebo subjects (p<0.001, 1 sided).Moreover, subjects treated with gaboxadol on average had 20.53 minutesof SWS longer than those treated with placebo on the last two SleepRestriction nights.

Finally, this study examined the efficacy of gaboxadol compared toplacebo during the last 2 nights/days of sleep restriction in: (1)improving memory and attention as assessed by a neurobehavioral battery;(2) reducing subjective sleepiness as measured by the KarolinskaSleepiness Score (KSS); (3) altering sleep parameters (e.g., total sleeptime, latency to onset of Slow Wave Sleep (SWS), slow wave activity(SWA); and (4) reducing biological stress typified by increased heartrate variability, and decreased cortisol levels and decreasedcatecholamine levels, as well as decreased body temperature.

There was a trend towards less subjective daytime sleepiness for thegaboxadol subjects during the Sleep Restriction period as compared withplacebo subjects. The Karolinska Sleepiness Score (KSS) was on average0.68 less for subjects treated with gaboxadol than for those treatedwith placebo on the last two Sleep Restriction days (p=0.058, 1 sided)as evaluated by a Longitudinal data analysis (LDA) model with adjustmentfor baseline KSS, gender, and age. A supportive analysis usingcovariance (ANCOVA) also supports this finding. The effect sizescomputed for the neurocognitive battery showed that there was no strongevidence that gaboxadol improves daytime performance. There were nodifferences between gaboxadol and placebo with respect tobiophysiological measures of stress (heart rate variability, cortisollevels, catecholamine levels, body temperature).

Compared with placebo, gaboxadol has a protective effect on reducingdaytime sleepiness as measured by the MSLT on the last 2 days of4-nights of sleep restriction. Compared with placebo, gaboxadolincreases the amount of slow wave sleep (SWS) during the last 2 nightsof 4-nights of sleep restriction.

Example 5

Prospective Assessment of Delirium and Long-Term NeuropsychologicalDysfunction

This study is used to compare sedation and analgesia for ventilatedintensive care unit (ICU) patients treated with an alpha2 agonist (e.g.,dexmedetomidine) or a GABA-Agonist (e.g., propofol, lorazepam,midazolam, gaboxadol). In particular, this study is used to assess thedelirium rates, efficacy of sedation, analgesia and discharge cognitivestatus of patients that have undergone sedation therapy. The study isalso be used to compare clinical outcomes including duration ofmechanical ventilation, ICU length of stay and severity ofneuropsychological dysfunction at hospital discharge. In addition, thestudy is used to develop pharmacokinetic and pharmacodynamic models forgaboxadol in ICU patients.

This study may include adult patients admitted to the medical andsurgical ICU for critical illnesses requiring mechanical ventilation.The patients may have an expectation of being mechanically ventilatedfor greater than 24 hours. In this study patients will receive a bolusdose over a specific period of time, e.g., 10 minutes, followed by aninfusion of gaboxadol or a comparator drug (e.g., dexmedetomidine,propofol, lorazepam). A comparison of each sedative is established byfirst setting a “goal” or “target” sedation level as medically indicatedusing Richmond Agitation-Sedation Scale. The “actual” RASS level maythen be measured every 12 hours. Comparisons are made between the actualand target RASS levels to determine the primary outcome measure, whichis the accuracy of achieving the target sedation level.

In addition, the duration and severity of delirium is measured using theCAM-ICU every 12 hours. Delirium is said to be present if the patientsare responsive to verbal stimulation with eye opening (e.g., RASS −3 orbetter) and are found to have an acute change or fluctuation in thecourse of their mental status, inattention, and either disorganizedthinking or an altered level of consciousness. Assessments may alsoinclude the Johns Hopkins Adapted Cognitive Exam: Cognitive assessmenttoolConfusion Assessment Method for the Intensive Care Unit, CAM-ICUdelirium assessment tool; and/or the time from initiation of study drugto calm, non-anxious state.

Example 6

Prospective Assessment of the Safety and Efficacy of Gaboxadol forSedation During Monitored Anesthesia Care

This study includes adult patients (>18 years of age) that areclassified in American Society of Anesthesiologists (ASA) PhysicalStatus I, II, III, or IV and require Monitored Anesthesia Care in anoperating room or procedure room with an anesthesiologist in attendance.The patients would also require an elective surgery/procedure expectedto take longer than 30 minutes.

The patient will be administered intravenous gaboxadol and one or moreoutcome measures will be observed. For example, one such outcome measuremay include the percent of patients not requiring rescue sedation basedon achieving and/or maintaining an Observer's Assessment ofAlertness/Sedation Scale (OAA/S) score <4. Other outcomes that may beobserved include measurements of the total amount (mg) of rescuesedation medication (e.g., midazolam, propofol) required to achieveand/or maintain sedation (OAA/S score <4); the time from onset ofgaboxadol infusion to first dose of rescue medication (e.g., midazolam,propofol); the percentage of subjects who convert to alternativesedative and/or anesthetic therapy due to failure of treatment withstudy drug and rescue; the time to recovery and readiness for dischargefrom Post-Anesthesia Care Unit (PACU); an anesthesiologist assessment ofease of management; the incidence of post-operative nausea and vomitingin the PACU; and/or subject satisfaction and anxiety assessed 24 hoursafter administration of gaboxadol.

Example 7

Prospective Assessment of the Safety and Efficacy of Gaboxadol forIntensive Care Unit Sedation

This study includes adult patients (>18 years of age) being treated in asurgical intensive care unit. All patients may be initially intubatedand receive mechanical ventilation. This study is used to evaluate thesedative properties of gaboxadol by comparing the amount of rescuemedication (e.g., midazolam or propofol) required to achieve a specifiedlevel of sedation (using the standardized Ramsay Sedation Scale) betweengaboxadol and placebo from onset of treatment to extubation or to atotal treatment duration of 24 hours.

The Ramsay Level of Sedation Scale (RSS) is a test of rousability at sixdifferent levels. It lends itself to universal use, not only in the ICU,but wherever sedative drugs or narcotics are given. It can be added tothe pain score and be considered the sixth vital sign.

Ramsay Sedation Scale:

1 Patient is anxious and agitated or restless, or both

2 Patient is co-operative, oriented, and tranquil

3 Patient responds to commands only

4 Patient exhibits brisk response to light glabellar tap or loudauditory stimulus

5 Patient exhibits a sluggish response to light glabellar tap or loudauditory stimulus

6 Patient exhibits no response

The invention claimed is:
 1. A method of sedating a human patient duringtreatment in an intensive care setting comprising intravenouslyadministering to the patient a pharmaceutical composition of gaboxadolor a pharmaceutically acceptable salt thereof wherein the gaboxadol or apharmaceutically acceptable salt thereof is administered at an infusionrate of between about 0.25 to about 100 μg/kg/min.
 2. The method ofclaim 1, wherein the patient is undergoing treatment in an intensivecare setting and the treatment is selected from the group consisting ofintensive care sedation, sedation of the patient prior to surgery,procedural sedation, monitored anesthesia care, moderate sedation andconscious sedation.
 3. The method according to claim 1, wherein thetreatment in the intensive care setting is monitored anesthesia care. 4.The method according to claim 1, wherein the gaboxadol is administeredas a continuous infusion.
 5. The method according to claim 1, whereinthe gaboxadol is administered as a bolus dose.
 6. The method accordingto claim 1, wherein the gaboxadol or a pharmaceutically acceptable saltthereof is administered at an infusion rate of between about 0.25μg/kg/min to about 25 μg/kg/min.
 7. The method according to claim 1,wherein the gaboxadol or a pharmaceutically acceptable salt thereof isadministered at an infusion rate of between about 1 μg/kg/min to about50 μg/kg/min.
 8. The method according to claim 1, wherein the gaboxadolor a pharmaceutically acceptable salt thereof that provides an in vivoplasma profile comprising a Cmax less than about 350 ng/ml.
 9. Themethod according to claim 1, wherein the gaboxadol or a pharmaceuticallyacceptable salt thereof that provides an in vivo plasma profilecomprising a Cmax less than about 250 ng/ml.
 10. The method according toclaim 1, wherein about 0.1 to about 50 mg of gaboxadol or apharmaceutically acceptable salt thereof is administered over 24 hours.11. The method according to claim 1, wherein about 0.1 to about 25 mg ofgaboxadol or a pharmaceutically acceptable salt thereof is administeredover 24 hours.
 12. The method according to claim 1, wherein about 0.1μg/kg to about 10 μg/kg of gaboxadol or a pharmaceutically acceptablesalt thereof is administered over 24 hours.
 13. The method according toclaim 1, wherein about 0.1 μg/kg to about 5 μg/kg of gaboxadol or apharmaceutically acceptable salt thereof is administered over 24 hours.14. The method according to claim 1, wherein the gaboxadol isco-administered with an anesthetic, sedative, hypnotic or opioid.
 15. Amethod of sedating a human patient during treatment in an intensive caresetting selected from the group consisting of intensive care sedation,sedation of the patient prior to surgery, procedural sedation, monitoredanesthesia care, moderate sedation and conscious sedation comprisingintravenously administering to the patient a pharmaceutical compositionof gaboxadol or a pharmaceutically acceptable salt thereof wherein about0.1 to about 50 mg of gaboxadol or a pharmaceutically acceptable saltthereof is administered over 24 hours.
 16. The method according to claim15, wherein the gaboxadol or a pharmaceutically acceptable salt thereofis administered at an infusion rate of between about 0.001 μg/kg/min toabout 5 μg/kg/min.
 17. A method of sedating a human patient duringtreatment in an intensive care setting comprising intravenouslyadministering to the patient a pharmaceutical composition of gaboxadolor a pharmaceutically acceptable salt thereof that provides an in vivoplasma profile comprising a Cmax less than about 350 ng/ml.
 18. Themethod of claim 17, wherein the patient is undergoing treatment in anintensive care setting and the treatment is selected from the groupconsisting of intensive care sedation, sedation of the patient prior tosurgery, procedural sedation, monitored anesthesia care, moderatesedation and conscious sedation.
 19. The method according to claim 17,wherein the treatment in the intensive care setting is monitoredanesthesia care.
 20. The method according to claim 17, wherein thegaboxadol is administered as a continuous infusion.
 21. The methodaccording to claim 17, wherein the gaboxadol is administered as a bolusdose.
 22. The method according to claim 17, wherein the gaboxadol or apharmaceutically acceptable salt thereof is administered at an infusionrate of between about 0.25 to about 25 μg/kg/min.
 23. The methodaccording to claim 17, wherein the gaboxadol or a pharmaceuticallyacceptable salt thereof is administered at an infusion rate of betweenabout 0.001 to about 5 μg/kg/min.
 24. The method according to claim 17,wherein the gaboxadol or a pharmaceutically acceptable salt thereof isadministered in an amount of about 10 μg/kg to 1000 μg/kg as a singlebolus dose.
 25. The method according to claim 17, wherein the gaboxadolor a pharmaceutically acceptable salt thereof is administered in anamount of about 100 to about 250 μg/kg as a single bolus dose.
 26. Themethod according to claim 17, wherein about 0.1 to about 50 mg ofgaboxadol or a pharmaceutically acceptable salt thereof is administeredover 24 hours.
 27. The method according to claim 17, wherein about 0.1to about 25 mg of gaboxadol or a pharmaceutically acceptable saltthereof is administered over 24 hours.
 28. The method according to claim17, wherein about 0.1 μg/kg to about 10 μg/kg of gaboxadol or apharmaceutically acceptable salt thereof is administered over 24 hours.29. The method according to claim 17, wherein about 0.1 μg/kg to about 5μg/kg of gaboxadol or a pharmaceutically acceptable salt thereof isadministered over 24 hours.
 30. The method according to claim 17,wherein the gaboxadol or a pharmaceutically acceptable salt thereofprovides an in vivo plasma profile comprising a Cmax less than about 350ng/ml.